This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of improved inhibitors of a drug target can be aided by detailed knowledge of its three-dimensional structure. Using data collected at BNL-NSLS, bemline X25 we plan to determine structures of HIV-1 RT in the presence and absence of both RNA/DNA and DNA/DNA in complex with a variety of inhibitors including: nucleoside/nucleotide analogs (NRTIs), specific RNase H inhibitors (RNHIs), and non-nucleoside RT inhibitors (NNRTIs) that would enable structure-based design of potential new anti-HIV drugs. Additionally we plan to use high resolution X-ray crystal structures of HIV-1 RT to carry out a drug fragment cocktail screening project designed to identify new lead compounds for existing drug-binding sites as well as discovering new inhibitor binding pockets. We also plan to pursue structural studies of bacterial RNA polymerase (RNAP) in complexes with various nucleic acid constructs and antibiotics to expand our understanding of the inhibitory behavior of these compounds on RNAP function.